Studies of the pathogenesis of atherosclerotic lesions have been guided by several hypotheses: the cholesterol hypothesis has been central for many years and has provided fruitful However, there has developed appreciation of the fact that the process involves more than lipid deposition and that vascular injury may be caused by various agents such as oxidized lipids, viruses, oxygen free radicals and substances other than lipids may gain access to vessel walls via the blood. It has become evident that the various injurious agents invoke a large interconnected network of factors responsible for defending against a wide range of different insults. Moreover, for survival of an organism the responses evoked by various forms of injury must maintain a balance between destroying or removing a noxious entity and limiting the destructive effects of this part of the defense system. The main peptide in the amyloid substance of "reactive' type of amyloid derive from circulating precursors, serum amyloid A proteins secreted by the liver and associated with HDL lipoproteins, i.e. as apoSAAs. Furthermore they are produced locally by a variety of cells including those of the type involved in development of atherosclerotic plaque such as endothelial cells, vascular smooth muscle, and macrophages. Several functions seem to be emerging for products of this ancient family of genes including sequestration of lipid-soluble toxins, redirection of HDL cholesterol transport, interference with platelet aggregation and inhibition of leukocyte functions. We propose to examine, using in vivo and in vitro experiments, the potential modulator activities of the apoSAAs in relation to local reactions to injurious agents such as may be driving development of lesions of atherosclerosis.